Back to EveryPatent.com
| United States Patent |
5,744,634
|
|
Veits
|
April 28, 1998
|
Process for producing 2-keto-L-gulonic acid esters
Abstract
A process for the manufacture of methyl or ethyl 2-keto-L-gulonate by
esterifying 2-keto-L-gulonic acid with methanol or ethanol continuously in
the presence of an acidic ion exchanger in the temperature range between
room temperature and about 80.degree. C. and with average residence times
between about 10 and about 120 minutes and with superficial velocities of
about 0.5 m/h to about 7.5 m/h. The esterification is advantageously
carried out under slight over-pressure. The thus-manufactured esters are
important intermediates for the synthesis of vitamin C and the respective
esterification product can be converted directly into vitamin C by
lactonization.
| Inventors:
|
Veits; Joachim (Rheinfelden, DE)
|
| Assignee:
|
Roche Vitamins Inc. (Parsippany, NJ)
|
| Appl. No.:
|
858639 |
| Filed:
|
May 19, 1997 |
Foreign Application Priority Data
| Current U.S. Class: |
560/174; 560/186 |
| Intern'l Class: |
C07C 069/66 |
| Field of Search: |
560/186,174
|
References Cited
U.S. Patent Documents
| 5128487 | Jul., 1992 | Tomislav et al. | 549/315.
|
| Foreign Patent Documents |
| 0138436 | Apr., 1985 | EP.
| |
| 0403351 | Dec., 1990 | EP.
| |
| 0535927 | Sep., 1992 | EP.
| |
| 1260927 | Jan., 1972 | DE.
| |
Other References
Chemical Abstract 64:12784C.
English Abstract for EP# 0 403 351.
Drefahal, J. Prakt. Chem. Bd. 1, pp. 153-156 (1955).
T.A. Melentyeva, et al. Chemical Abstracts, 271553f vol. 119, No. 25
(1993).
Derwent Abstract Basic No. 19,401 (1965).
Gao et al, Kinetics of esterification of 2 keto L gulonic acid with
methanol on ion exchange resin catalyst, Fudan Xuebao, Ziran Kexueban
(1986) 25(2) 163 8.
|
Primary Examiner: Geist; Gary
Assistant Examiner: Keys; Rosalynd
Attorney, Agent or Firm: Johnston; George W., Epstein; William H., Kreisler; Lewis J.
Parent Case Text
This is a continuation of application Ser. No. 08/349,159 filed Dec. 2,
1994, abandoned.
Claims
I claim:
1. A process for the manufacture of methyl or ethyl 2-keto-L-gulonic acid
ester comprising:
reacting 2-keto-L-gulonic acid with a lower alkanol selected from the group
consisting of methanol and ethanol to form a reaction mass, and
exposing the reaction mass to an acidic ion exchanger to produce said
ester, at a temperature from about room temperature to about 80.degree. C.
continuously for a time from about 10 minutes to about 120 minutes,
wherein said exposing is characterized by flowing the reaction mass over
the ion exchanger to produce a flow having a superficial velocity from
about 0.5 m/h to about 7.5 m/h.
2. The process of claim 1, wherein the ion exchanger is AMBERLYST.RTM. 15.
3. A process of claim 1, wherein the exposing is carried out at
temperatures from about 55.degree. C. to about 65.degree. C. continuously
for a time from about 10 minutes to about 20 minutes.
4. A process of claim 1, wherein said exposing is carried out under an
over-pressure up to maximum of 4 bar.
5. The process of claim 1, wherein the lower alkanol is methanol.
6. A process of claim 5, wherein the concentration of 2-keto-L-gulonic acid
in methanol is in the range of from about 8 to about 15 weight percent.
7. The process of claim 6, wherein the exposing is carried out at a
temperature about 60.degree. C. for a time up to a maximum of 20 minutes.
Description
BACKGROUND OF THE INVENTION
The esterification of 2-keto-L-gulonic acid with a lower alkanol,
especially methanol, is known from numerous publications. One such
esterification is usually carried out in the presence of an acidic
catalyst, e.g. hydrochloric acid, sulphuric acid or p-toluenesulphonic
acid. After the esterification to the corresponding lower alkyl ester,
this lower alkyl ester can be subjected to an alkaline rearrangement (or
lactonization) to produce ascorbic acid or a salt thereof, usually the
sodium or potassium salt.
Occasional references to the esterification of 2-keto-L-gulonic acid in the
presence of an ion exchanger as the acidic catalyst are found in the
technical literature. However, in most cases details of yields,
conversions etc. are missing or the reported results, e.g. with respect to
yields and crystal quality, are unsatisfactory. Moreover, these processes
require long reaction times and often high reaction temperatures. A
process for the continuous esterification of 2-keto-L-gulonic acid has
hitherto not been carried out or has not been published.
Basically, an esterification process for the manufacture of a
2-keto-L-gulonic acid ester, especially the methyl or ethyl ester, should
be simple to carry out, gentle and should proceed with high conversion
(produce high yields), and be a continuous procedure.
Such an esterification process which fulfils the stated requirements to a
high degree and which has advantages over conventional processes has now
been found. The process in accordance with the invention for the
esterification of 2-keto-L-gulonic acid with methanol or ethanol to its
methyl or ethyl ester comprises carrying out the esterification
continuously in the presence of an acidic ion exchanger in the temperature
range between room temperature and about 80.degree. C. and with average
residence times between about 10 and about 120 minutes and with
superficial velocities of about 0.5 m/h to about 7.5 m/h (h=hour),
optionally under slight over-pressure.
SUMMARY OF THE INVENTION
The present invention is concerned with a novel process for the manufacture
of 2-keto-L-gulonic acid esters. As is known, these esters are important
intermediates for the synthesis of ascorbic acid (vitamin C). This process
comprises esterifying 2-keto-L-gulonic acid with methanol or ethanol
continuously in the presence of an acidic ion exchanger at temperatures
from about room temperature to about 80.degree. C. and with average
residence times from about 10 to about 120 minutes, and with superficial
velocities of about 0.5 m/h to about 7.5 m/h, optionally under slight
over-pressure.
BRIEF DESCRIPTION OF THE DRAWING
FIG. 1 is a schematic representation depicting the apparatus used for
esterifying 2-keto-L-gulonic acid in accordance with the invention.
DETAILED DESCRIPTION OF THE INVENTION
This invention is directed to a novel process for esterification of
2-keto-L-gulonic acid (2-KLGA) with methanol or ethanol. This process
comprises esterifying 2-KLGA with methanol or ethanol continuously in the
presence of an acidic ion exchanger at temperatures from about room
temperature to about 80.degree. C., with average residence times from
about 10 minutes to about 120 minutes and with superficial velocities of
about 0.5 m/h to about 7.5 m/h, optionally under slight over-pressure.
Essentially, the esterification is carried out by allowing a solution of
2-keto-L-gulonic acid in methanol or ethanol to continuously flow over the
acidic ion exchanger situated in a reactor, such as depicted as (6) in FIG.
1. The esterification is generally carried out in the temperature range
from about room temperature to about 80.degree. C. with average residence
times in the reactor from about 10 to 120 minutes. Best results are
obtained at temperatures from about 55.degree. C. to about 65.degree. C.,
and with average residence times from about 10 to about 120 minutes. With
regard to overall conversion of 2-keto-L-gulonic acid to an ester, it is
generally true that higher temperatures necessitate shorter average
residence times. Moreover, the esterification taking place in the reactor
is conveniently effected under a slight over-pressure up to a maximum of 4
bar, independently of the esterification temperature. With regard to the
overall conversion, there is a slight dependence on the esterification
temperature and the concentration of 2-keto-L-gulonic acid in the methanol
or ethanol. For example, with concentrations in the range of about 8 to
about 15 weight percent of 2-keto-L-gulonic acid in methanol the
esterification proceeds (almost) ideally at about 60.degree. C. and with
residence times of less than 20 minutes. Under such conditions the
residual 2-keto-L-gulonic acid content is normally a maximum of 1%.
In general, the esterification in accordance with the invention is carried
out with concentrations of about 2.5 to about 15 weight percent of
2-keto-L-gulonic acid in methanol or ethanol. When methanol is used, the
concentration conveniently lies in the range of 8 to 15 weight percent
(wt./wt. %), which corresponds to a concentration, expressed in
weight/volume percent (wt./vol. %), of 7 to 14 wt./vol. % based on
anhydrous 2-keto-L-gulonic acid. The 2-KLGA to be esterified can be used
as anhydrous or hydrated 2-keto-L-gulonic acid (especially the monohydrate
form). The anhydrous form is, however, preferred. It has been found that,
at least in the concentration range 8 to 12.2 wt./wt. % of the
2-keto-L-gulonic acid in methanol, the esterification proceeds practically
independently of the concentration: the course of the reaction in this
concentration range is almost constant (zero or pseudo-zero order reaction
with respect to the 2-keto-L-gulonic acid).
In the above definition of the invention the term "acidic ion exchanger"
embraces any acidic ion exchanger known in the art, such as the
commercially available DUOLITE.RTM. C 20, C 26, C 264 and C 265 (all Rohm
& Haas); AMBERLITE.RTM. 18 wet and IRA 120 (also Rohm & Haas);
AMBERLYST.RTM. 15 (Rohm & Haas); LEWATIT.RTM. S 100 and SP 112 (Bayer); as
well as DOWEX.RTM. ion exchanger I (Dow). AMBERLYST.RTM. is the best suited
of these acidic ion exchangers for the purpose of the present invention.
Basically, any other acidic ion exchangers can, of course, also be used in
accordance with this invention to esterity 2-KLGA with methanol or ethanol.
The term "superficial velocity" which also appears in the definition of the
invention is known in the art and denotes the flow velocity with which a
liquid reaction mass, i.e., 2-KLGA in methanol or ethanol, flows through a
tube-like or column-like reactor filled with the acidic ion exchanger and
which, as explained hereinafter, depends on the throughput volume and on
the cross section of the reactor tube. This velocity is connected in the
wider sense with the average effective velocity. This is expressed
mathematically as follows:
##EQU1##
in which V.sub.superficial is expressed as cm/h or m/h.
As mentioned above, the superficial velocity V.sub.superficial is directly
connected with the so-called average effective velocity V.sub.effective,
namely according to the equation:
##EQU2##
These terms are explained in more detail inter alia in the textbook
"Thermische Verfahrenstechnik" by A. Mersmann, p. 99 et seq.,
Springer-Verlag Berlin Heidelberg, New York 1980.
As mentioned above, the superficial velocity is, inter alia, an essential
feature of the invention. When it has a range of about 0.5 m/h to about
7.5 m/h, this corresponds to an average effective velocity of about 0.9 to
about 14.5 m/h.
A typical installation for the esterification process in accordance with
the invention is shown schematically in FIG. 1, with the given dimensions
applying to a small scale plant. On a commercial scale appropriately
larger dimensions will, of course, apply.
The process in accordance with the invention has several advantages,
namely:
the procedure is continuous and accordingly is efficient to carry out;
the residence times are relatively short in comparison to previous
esterifications of 2-keto-L-gulonic acid with methanol or ethanol;
the practical (with respect to apparatus) performance of the process is
simple and economical, especially, for example, because neither water
removal for equilibrium displacement nor high reaction temperatures are
required;
the corrosion of a metal-containing reaction vessel is avoided, since the
catalyst used to carry out the esterification is not a mineral acid, e.g.
hydrochloric acid, sulphuric acid etc.;
the equilibrium conversions are high, the product having, depending on the
specific reaction conditions, a residual unreacted 2-keto-L-gulonic acid
content of only about 0.5 to 1.5 weight percent; and
the esterification product can be used directly, i.e. without isolating the
methyl or ethyl 2-keto-L-gulonate, in the lactonization step for the
manufacture of the desired ascorbic acid, e.g. under alkaline conditions
(using, for example, sodium bicarbonate, sodium hydroxide, sodium
methoxide or trihexylamine as the base).
The process in accordance with the invention also embraces various
procedural variants of the above-described, relatively simple procedure
with the object of increasing the nevertheless very high equilibrium
conversion even more. For example, the reaction mixture can pass through
several (two or more) interconnected reactors until the desired
(especially high) conversion has been achieved. Further, after passage
through a reactor a partial intermediate evaporation, i.e. partial removal
of water with the same alkanol, e.g. methanol, can be carried out and the
reaction mixture can subsequently be passed through a connected
esterification column with or without the addition of fresh methanol or
ethanol.
The process in accordance with the invention is illustrated on the basis of
the following Examples, each of which refers to the aforementioned typical
apparatus for esterification diagrammatically presented in FIG. I.
EXAMPLE 1
917.45 g of 2-keto-L-gulonic acid (hereinafter "2-KLGA"; 98.1% quality) and
10 L (liters) of methanol are introduced, in each case in 2 portions, into
a 10 L glass vessel and stirred until a homogeneous solution has formed.
The mixture is filtered clear over a 0.2 .mu.m GELMAN membrane filter and
the solution is transferred portionwise into the supply vessel (3). If
desired, the supply vessel is heated at a temperature of 35.degree. C.
using a thermostat (1).
Then, the mixture is withdrawn via a bottom valve and pumped using a LEWA
M8 membrane pump (5) with an input velocity of 800 ml/h firstly over a
small pre-column (11) filled with AMBERLYST.RTM. 15 and thereafter through
the exchanger bed situated in a double jacketed reactor (6) and heated to
60.degree.-62.degree. C. The filled pre-column has a protective function
in that it captures traces of metal, e.g. iron, copper, zinc. etc. The
heating of the column is effected at a temperature of 63.degree. C. by
means of a thermostat (2). In order to avoid boiling effects and the
formation of gas bubbles, the apparatus is adjusted to 0.4-0.6 bar
over-pressure (7) with a pressure sustaining valve (8) installed at the
column exit. In order to control the conversion, samples are withdrawn at
intervals of 2 hours and in each case the residual 2-KLGA content is
determined by HPLC. Parallel to this, a control of the input amount is
performed using a graduated 50 ml shaking cylinder. Under the given
conditions the superficial velocity is 2.86 m/h and the average effective
velocity is 5.53 m/h. The average residence time is about 14.6 minutes.
After passage of the mixture a further 3 L of methanol are pumped through
in order to rinse the apparatus.
In order to isolate the thus-manufactured methyl 2-keto-L-gulonate
(hereinafter "Me-2-KLGA"), the esterification solution collected in the
receiving vessel (9) is concentrated in a BUCHI Rotavapor Type R 152 at a
bath temperature of 50.degree. C. and a pressure of 200 mbar to a crystal
slurry (about 67 wt./wt. % Me-2-KLGA) and cooled at 40.degree. C. for
about 4 hours for further crystallization. The crystallizate is thereupon
suction filtered over a sintered glass suction filter and rinsed twice
with 500 ml of methanol (-10.degree. C.) each time. Drying is effected at
50.degree. C. and 10-15 mbar within 12 hours. Yield: 1700-1800 g of 1st
cristallizate of Me-2-KLGA, quality.gtoreq.99.5%.
In order to isolate the 2nd crystallizate, the mother liquor is likewise
concentrated at 50.degree. C. and 200 mbar to a crystal slurry (about 43
wt./wt. % Me2-KLGA content), cooled at 4.degree. C. over 4 hours and the
crystallizate is suction filtered over a sintered glass suction filter.
Then, the product is rinsed twice with 130 ml of methanol (-10.degree. C.)
each time and dried at 50.degree. C. under a vacuum for about 12 hours.
Yield: about 100 g of 2nd crystallizate of Me-2-KLGA, quality>98.0%.
The overall conversion to Me-2-KLGA amounts to 97.5-97.9% (quantified by
means of HPLC) starting from 2-KLGA and without the ascorbic acid formed
as a byproduct, and 95.7-95.9% of theory of Me-2-KLGA are isolated as
colourless crystals from the practically colourless esterification
solution (1st and 2nd crystallizate, quality already considered).
Isolation of the crystals need not be effected, since the solution can be
used, if desired, directly for the manufacture of ascorbic acid, e.g. by
alkaline rearrangement (lactonization).
EXAMPLE 2
As described in Example 1, a 10.2 wt./wt. % solution of 2-KLGA in methanol
is pumped through the column at a temperature of 30.degree. C. and with a
superficial velocity of 0.63 m/h and an average residence time of about
116 minutes. Conversion to a residual 2-KLGA content of about 5.1% takes
place. A repeated passage of the solution under the same conditions, i.e.
without intermediate partial removal of methanol/water, leads to a
residual 2-KLGA content of about 1.6%.
EXAMPLE 3
As described in Example 1, a 10.2 wt./wt. % solution of 2-KLGA in methanol
is pumped through the column at a temperature of 60.degree.-62.degree. C.
and with a superficial velocity of about 5.7 m/h (corresponding to an
average effective velocity of about 11 m/h) and a residence time of about
6.5 min. Conversion to a residual 2-KLGA content of about 7.3-9.1% takes
place. A repeated passage of the solution under the same conditions leads
to a residual 2-KLGA content of about 1.3-1.7%. The total residence time
is thus 2.times. about 6.5 min., i.e. about 13 min.
EXAMPLE 4
Several 2-KLGA esterifications are carried out analogously to the procedure
described in Example 1 under diverse conditions. The respective details are
compiled in Table 1 hereinafter.
TABLE 1
______________________________________
Typical Examples/Results of esterification at 60-62.degree. C. (ideal
range)
Average
Residence Superficial
effective
Residual
Concentration
time velocity velocity
2-KLGA
wt./wt. %!
min! m/h! m/h! %!
______________________________________
8.2 29.0 1.27 2.45 0.42
19.5 1.91 3.69 0.42
14.5 2.54 4.91 1.40
10.2 23.5 1.59 3.07 0.63
16.7 2.23 4.31 0.65
14.6 2.86 5.53 0.80
13.0 3.50 6.77 0.96
12.2 29.0 1.27 2.45 0.91
19.5 1.91 3.69 1.00
14.5 2.54 4.91 1.32
15.0 29.0 1.27 2.45 0.90
19.5 1.91 3.69 1.10
14.5 2.54 4.91 1.35
______________________________________
EXAMPLE 5
Further 2-KLGA esterifications (Tests 1-6) are carried out analogously to
the procedure described in Example 1. The average residence time in this
case is about 14.6 min. and the superficial velocity is about 2.86 m/h.
The other relevant details are compiled in Table 2 hereinafter:
TABLE 2
__________________________________________________________________________
Batch: 1800 g of 2-KLGA gives 1929.6 g of Me-2-KLGA according to theory
Notation (T = test) T 1 T 2 T 3 T 4 T 5 T 6
__________________________________________________________________________
Residual 2-KLGA.sup.1)
%!
0.82
0.86
0.70
0.85
0.85
0.82
1st crystallizate Me-2-KLGA
Yield g!
1678.9
1731.0
1752.8
1793.0
1818.6
1754.9
Content %!
99.5
99.8
99.6
98.5
99.4
99.4
Amount (10 g!
1670.1
1727.5
1745.8
1766.1
1807.7
1743.4
Theoretical amount
%!
86.6
89.5
90.5
91.5
93.7
90.4
2nd crystallizate Me-2-KLGA
Yield g!
178.0
118.4
101.7
79.6
57.1
107.0
Content %!
98.0
98.8
96.8
94.3
94.0
96.4
Amount (100%) g!
174.4
117.0
98.4
75.1
53.7
103.7
Theoretical amount
%!
9.0 6.1 5.1 3.4 2.8 5.4
Mother liquor 2
Me-2-KLGA content
g!
54.1
40.5
44.1
27.4
40.4
41.3
Theoretical amount
%!
2.8 2.1 2.3 1.4 2.1 2.1
Balancing
Me-2-KLGA isolated. total (100%)
g!
1844.5
1844.5
1844.2
1841.2
1861.4
1847.2
Theoretical amount
%!
95.6
95.6
95.6
95.4
96.5
95.7
Amount of Me-2-KLGA. Total
g!
1898.6
1885.0
1888.3
1868.3
1901.8
1888.5
Theoretical amount Total
%!
98.4
97.7
97.9
96.8
98.6
97.9
__________________________________________________________________________
.sup.1) These values were determined by standardization from the peak
areas Me2-KLGA, ascorbic acid and 2KLGA.
Top